Spatial distribution of tissue inhibitor of metalloproteinase-1 mRNA in chronic liver disease

Background/Aims: Tissue inhibitor of metalloproteinase-1, a specific inhibi tor of matrix metalloproteinases, plays an important role in the pathogenes is of fibrosis and tumor progression. However, the precise expression of ti ssue inhibitor of metalloproteinase-1 messenger RNA in human hepatic fibros is has not yet been defined. We investigated the spatial distribution of ti ssue inhibitor of metalloproteinase-1 messenger RNA in chronic human liver disease. Methods: Northern and in situ hybridization of probes to tissue inhibitor o f metalloproteinase-1 messenger RNA were performed in specimens from 16 sur gically resected human livers. Immunohistochemical staining of sections for tissue inhibitor of metalloproteinase-1 and immunoelectron microscopy were also performed. Results: Northern hybridization demonstrated that expression of tissue inhi bitor of metalloproteinase-1 messenger RNA was increased 3.9-fold in mild c hronic hepatitis, 6.8-fold in moderate chronic hepatitis, and 6.4-fold in c irrhosis, compared with control liver. In situ hybridization showed the exp ression of tissue inhibitor of metalloproteinase-1 messenger RNA in spindle -shaped cells in the fibrous septa and lobules in chronic hepatitis and cir rhosis; these cells were immunohistochemically positive for alpha-smooth mu scle actin. Immunoelectron microscopy revealed localization of tissue inhib itor of metalloproteinase-1 in between fibers, to the rough endoplasmic ret icula of stellate cells located in the lobules and periportal areas, and to fibroblasts in the fibrous septa. These results indicate that tissue inhib itor of metalloproteinase-1 was produced mainly by stellate cells in the sp ecimens of chronic liver diseases. Conclusions: Expression of tissue inhibitor of metalloproteinase-1 messenge r RNA is increased in hepatic fibrosis and stellate cells are involved prim arily in its expression.